Project summary The molecular networks that specify cellular identity and suppress alternative cell fates are tightly regulated during normal tissue homeostasis but can become dramatically dysregulated during cancer progression. It has long been appreciated that tumor differentiation state often correlates with both intrinsic malignant potential and response to therapy. However, the master transcriptional regulators that control cellular identity in most cancer types remain to be elucidated. The long-term goal of this project is to determine how changes in cellular identity contribute to the progression of pancreatic ductal adenocarcinoma (PDAC). Pancreatic neoplasia adopts a foregut-like differentiation state that is distinct from normal pancreatic epithelial cells. We have observed that the differentiation state of pancreatic in situ neoplasia (PanIN) closely resembles that of mucinous lung adenocarcinoma, a type of lung cancer that also exhibits a foregut-like differentiation state. One of the foregut-associated transcripts expressed in both types of neoplasia is Hnf4?, a transcription factor that normally regulates the differentiation state of the gastrointestinal tract and liver. Using conditional murine genetics, we demonstrated that Hnf4? is a critical regulator of the growth and differentiation state of mucinous lung adenocarcinoma. In this proposal, we will test the hypothesis that Hnf4? regulates the differentiation state and malignant progression of pancreatic ductal adenocarcinoma using the following specific aims: (1) Determine the impact of Hnf4? loss on the differentiation and malignant progression of pancreatic ductal adenocarcinoma and (2) Characterize the mechanisms by which Hnf?? regulates the growth and differentiation state of pancreatic ductal adenocarcinoma.